Many neurotropic viruses are transmitted trans-synaptically, including measles, polio, rabies and some herpesviruses. Nevertheless, the viral protein-neuronal protein interactions that govern this process are not known. Moreover, while these viruses cause rapid, highly productive infections in the periphery, most are associated with chronic infections in the brain, likely due to reduced viral progeny production and cytopathology in neurons. Thus, the objectives of this proposal are to define how viruses, such as measles virus, interact with neuronal proteins to affect both intra- and inter-neuronal transport, and to establish how this mode of spread is associated with chronic central nervous system infections. These broad objectives will be accomplished through completion of two Specific Aims. In the first aim, intra-neuronal spread of measles virus to the synapse is studied, which will characterize the viral proteins that are present at synaptic membranes, and whether these proteins are required for trans-synaptic spread. In addition, interaction with cellular motor proteins that govern movement along microtubules will be determined. In the second aim, inter-neuronal measles transmission is addressed, and the role of a putative, novel fusion protein receptor, neurokinin-1, ascertained. Specifically, we will establish if neurokinin-1 is required for viral neurotransmission, whether the measles fusion protein and neurokinin-1 interact, and, ultimately, how blockade of this proposed interaction affects viral spread and pathogenesis in a susceptible transgenic mouse model. Successful completion of these aims will contribute to our long-term goals that include: (1) identification of cellular factors that contribute to viral persistence in neurons; (2) determination of how viral persistence may lead to host impairment without neuronal loss; and eventually (3) development of treatments to prevent or reverse the life- threatening consequences of chronic CNS infections. PUBLIC HEALTH RELEVANCE Viral infections of the central nervous system (CNS) are often associated with chronic neurological diseases, rather than the acute illnesses these viruses cause in the periphery. In this application, we focus on measles virus neuropathogenesis using novel mouse models, primary neuronal cell cultures, and human neuronal cell lines. The broad, long-term objectives of this proposal are to define how measles virus particles interact with neuronal proteins to affect both intra- and inter- neuronal viral transport, and to determine how spread across the synapse may contribute to neuropathogenesis. Successful completion of the proposed aims will provide the foundation for the development of treatments to prevent or reverse the life-threatening consequences of chronic CNS infections caused by viruses.